The carcinoembryonic cell adhesion molecule (CEACAM) family of proteins has been known for many years as intestinal tumor markers with a role in innate host defense in mucosa of several tissues, however there have been no previous detailed studies of CEACAMs in the lung. We initially identified CEACAM6 as an induced gene in human fetal lung epithelial cells undergoing hormone-stimulated differentiation into type II cells. Preliminary studies indicate that CEACAM6 is developmentally regulated during in vivo lung development and is induced synergistically by glucocorticoid and cAMP by a process involving thyroid transcription factor-1 (TTF-1), a key transcription factor in type II cells. In addition, CEACAM6 is found in tracheal aspirates of infants and adults, associated in part with secreted surfactant, and appears to be up-regulated in lung injury and infection. Based on these observations, the overriding hypothesis of this project is that CEACAM6 is a TTF-1-dependent, type II cell-specific protein that is involved in lung innate host defense. Three aims are proposed to investigate developmental and hormonal regulation as well as CEACAM6 function in the alveolus. The basic studies utilize a well characterized primary human cell culture system that is a highly relevant model for human lung development and disorders. Studies of Aim 1 will explore CEACAM6 interaction with surfactant and effects of CEACAM6 on apoptosis and innate immune properties of type II cells using adenovirus transduction and siRNA approaches for gain and loss of function. Aim 2 will investigate molecular mediators and mechanisms for increased expression of CEACAM6 during hormone-induced differentiation of human type II cells in vitro, characterizing the role of TTF-1 and other mediating factors and interactions with CEACAM6 promoter. Experiments of Aim 3 will determine the developmental pattern and regulatory mechanisms of CEACAM6 expression in human fetal lung and examine associations of postnatal levels in lung tissue, tracheal aspirates and plasma with lung disease of premature infants, utilizing a large repository of clinical samples and clinical data. Relevance to Public Health: This research addresses a previously unexplored lung protein (CEACAM6) that has important functions in other tissues related to host defense and cancer. The studies of this project will examine expression and function of the protein in normal lung and its role in response to lung injury and infection.